14800-DvRappard

31 Metachromatic leukodystrophy: disease spectrum and approaches for treatment 2 gastrostomy usually becomes necessary. Seizures are common. Painful spasms and general irritability are particularly challenging. Death occurs within a few years after the onset of symptoms. The late infantile form is genetically characterized by homozygosity or compound heterozygosity for alleles that do not allow the synthesis of functional enzyme, resulting in rapid accumulation of sulfatides and rapid disease progression. 8 In the juvenile variant, symptoms start between 2.5 and 16 years of age. The disease often begins with deterioration of school performance or behavior abnormalities. The first neurological signs are often ataxia and a mild pyramidal syndrome, leading to gait problems. Peripheral nerve damage may result in reduced deep tendon reflexes. 9 In the beginning, disease progression is slower than in the infantile onset form, but once the neurological signs become more evident, the decline is rapid and patients eventually lose all skills. 10 Spasticity becomes prominent, and many patients also develop epilepsy. The end stage of the disease can last several years, and its duration is variable. Patients suffering from the juvenile type mostly carry one allele that allows for expression of low amounts of residual enzyme activity. 8 The adult variant has an insidious onset after the age of 16 years. Intellectual and behavioral changes, such as memory deficits or emotional instability, are usually the first presenting symptoms. 9 Mild polyneuropathy develops in a later stage. Disease progression is generally slower than in the infantile and juvenile form. Death occurs within decades after disease onset. In the adult onset type, many patients carry two mildmutations, allowing for the expression of low amounts of functional enzyme, which delays the process of sulfatide accumulation and thereby the onset of the disease. 8 As more siblings in one family can be affected, it is important to test all siblings of the index patient for MLD regardless of their age as the age of disease onset can vary, especially for the juvenile or adult type. Non-neurological symptoms Apart from the neurological symptoms the accumulation of sulfatides can also cause symptoms in visceral organs. Gallbladder involvement is seen most often, leading to symptoms such as thickening of the gallbladder wall, gallstones, cholecystitis, and a small or enlarged gallbladder. 11 The diagnosis of MLD usually precedes the onset of gallbladder involvement, although cases have been reported in which gallbladder polyposis is the first symptom prompting the diagnosis. 11 Relatively little is known about gallbladder involvement in long term surviving MLD patients. Other organs that can be affected are liver, pancreas, intestines and kidneys. Case reports have also been written about disease expression in the adrenal glands, lymph nodes and ovaries. 12